DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Drawings
The drawings are objected to because hyaluronic acid structures in Figure 1 are poor quality in that the apparent brackets for the polymer repeating units are overlayed with apparent functional group symbols.
Appropriate correction is required.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 3, 4, 9, and 17 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claims reciting alternatives may be set forth as "a material selected from the group consisting of A, B, and C" or "wherein the material is A, B, or C". It is noted that amending the claim 3 to recite “…selected from the group consisting of galacturonic acid, glucuronic acid and iduronic acid” would obviate the rejection of claim 3, and likewise for claims 4, 9 and 17.
Claims 8 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 5 limits the iodinated moieties to “iodinated aromatic groups” while claim 8 depends of claim 5, but limits the “iodinated moieties” to “primary-amine-substituted iodinated compounds” which is confusing because of the contradictory use of “groups” to “compounds” in these claims. It is suggested that “compounds” in claim 8 is changed to “groups” to clarify.
Claims 20 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 20 recites the limitations "the kit " and “the reservoir” in the first line. There is insufficient antecedent basis for these limitations in the claim. It is not clear if claim 20 is drawn to the method of claim 15 or from the kit of claim 19. For the purposes of applying art below, claim 20 is being interpreted as depending from claim 19. It is suggested that claim 20 be changed to dependent from claim 19.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-7, 13-15, 19, and 20 are rejected under 35 U.S.C. 102(A)(1) as being anticipated by Lee et al. (Biomaterials 85, 2016).
Regarding claims 1 and 2, Lee discloses 2,3,5-Triiodobenzoic acid conjugated to hyaluronic acid (Figures 1, and 2A), a radiopaque hydrogel composition comprising a polysaccharide containing a plurality of radiopaque moieties that are covalently linked to a carboxylic-acid-containing polysaccharide along a backbone of the carboxylic-acid-containing polysaccharide through ester bonds.
Regarding claims 3 and 4, Lee discloses hyaluronic acid wherein the carboxylic-acid-containing polysaccharide naturally contains uronic acid species from glucuronic acid (Abstract).
Regarding claims 5-7 and 13, Lee teaches radiopaque moieties, covalently linked to a carboxylic-acid-containing polysaccharide backbone, that are iodinated aromatic groups substituted with an ester, a hydrophilic group that links the iodinated aromatic group to the polysaccharide backbone (Figs. 1 and 2A) providing a hydrogel having a radiopacity greater than 100 Hounsfield units (7A-24h post injection).
Regarding claims 14, 15, 19, and 20 Lee teaches an injectable radiopaque hydrogel in a reservoir that is inferred to be a syringe barrel as the hydrogel is injected into the mouse. (Section 2.8 CT imaging, lines 11-13, and Fig. 7 Caption). Clearly Lee discloses a kit comprising the hydrogel and a syringe reservoir since the hydrogel was injected into a mouse.
Claims 1-7, 14, 15, 19, and 20 are rejected under 35 U.S.C. 102(A)(1) as being anticipated by Pathak (US 2005/0036946A1).
Pathak teaches injectable radiopaque polysaccharide hydrogels (see para. 0105) where iodinated moieties are covalently linked to the polymer through ester and amide bonds (see para. 0108). A zero-length crosslinker, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), is disclosed for covalent bond formation between primary amine groups and carboxyl groups (see para. 107 and 108). The EDC linking chemistry is used to bind ditriozoate n-hydroxysuccinide ester (Figure 6) to natural polymers such as hyaluronic acid (see para 105), which naturally contains uronic acid species from glucuronic acid, through amide bonds (Figure 6). Two hydrophilic acetamido groups (–NHCOCH₃), as well as iodine substitutions, are contained on the aromatic ring of the polymer-linked iodinated compound (Figure 6). The radiopaque polysaccharide hydrogel disclosed by Pathak is clearly a kit containing the composition in a syringe as it is injectable (see para. 7 and 16).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-8, 10, 11, 14, 15, 19, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Pathak (US 2005/0036946A1) in view of Zhang et al. (ACS Biomater. Sci. Eng., 2022).
Pathak is disclosed above.
Pathak does not disclose primary-amine-substituted iodinated compounds.
Zhang discloses iodine hydrogel contrast agents consisting of aromatic moieties that are substituted with hydrophilic primary amine terminated functional groups and a plurality of iodine groups (Figure 1).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to implement the Iodinated aromatic moieties that are substituted with hydrophilic primary amine terminated functional groups of Zhang by covalently linking them the backbone of a carboxylic acid-containing polysaccharide using the method of Pathak. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because the EDC method of forming covalent bonds between primary amines and carboxyl groups is well-developed, especially for biological systems where reaction in water is needed, and the ability to create radiopaque hydrogels using the iodinated aromatic compounds of Zhang is clearly demonstrated.
Claim(s) 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Pathak and Zhang as applied to claims 1-8, 10, 11, 14, 15, 19, and 20 above, and further in view of Li et al. (Biomacromolecules, 2015).
Pathak and Zhang are discussed above.
Neither Pathak nor Zhang teach iodinated amino acid residues as radiopaque moieties.
Li teaches the synthesis and characterization of iodine-functionalized
phenylalanine, an amino acid, and polymers of phenylalanine diesters with primary amines (Abstract and Scheme 1).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the iodinated phenylalanine residue of Li into the hydrogel composition of Zhang by covalent attachment as disclosed by Pathak to yield the radiopaque contrast agent. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because the iodinated phenylalanine and phenylalanine diesters contain a primary amine terminus that could be linked to the carboxyl groups of the polysaccharide using the well-established EDC crosslinking chemistry as taught be Pathak.
Claim(s) 12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Pathak, Zhang, and Li as applied to claim 9, and further in view of Riaz et al. (Med Chem 2017).
Pathak, Zhang, and Li are discussed above.
Neither Pathak, Zhang nor Li teach extended-backbone amino acids such as beta-amino acids to provide a spacer between the iodinated moiety and the polysaccharide backbone. However, Li teaches the use of amino acid linkers as discussed above.
Riaz teaches beta-amino acids as vital building blocks for the preparation of pharmaceutical molecules (Title and Abstract) and, in the case of hydrogels, increased spacing between iodinated moieties and the polymer backbone would be expected to alter the water content of the composition and thus the physical properties relevant to injection and biodegradation in the subject.
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to substitute the amino acid linkers taught by Li with beta amino acids because beta amino acids are known to have remarkable pharmaceutical use as being antiketogenic, sterile and antifungal characteristics, as taught by Riaz, and they would provide additional spacing between the iodinated residues and the polymer backbone. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because the beta-amino acid has an amine terminus and a carboxyl terminus so that the EDC chemistry taught be Pathak could be used to covalently link iodinated moieties and the carboxyl acid-containing polysaccharide disclosed by Zhang by inserting the beta-amino acid between the iodinated moiety and the polysaccharide backbone.
Claim(s) 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Pathak and Zhang as applied to claims 1-8, 10, 11, 14, 15, 19, and 20 above, and further in view of Uman et al. (Adv. Healthcare Mater., 2020).
Pathak and Zhang are discussed above.
Neither Zhang nor Pathak disclose radiopaque compositions with radiopacity greater than 100 Hounsfield units.
Uman discloses a hyaluronic acid hydrogel where radiopacity is introduced by encapsulating the clinically used iodinated contrast agent, Omnipaque® Iohexol, GE Healthcare, to produce radiopaque compositions with radiopacity greater than 3000 Hounsfield units (Figure 4 B).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to predict a composition with a radiopacity greater than 100 Hounsfield units based on the disclosure of Uman describing a radiopacity greater than 3000 Hounsfield units The person of ordinary skill in the art would have been motivated to target a radiopacity greater than 100 Hounsfield units for the claimed composition and reasonably would have expected success because the disclosure of Uman using the same polysaccharide and a similar iodinated radiopaque moiety showed a radiopacity greater than 3000 units.
Claim(s) 16, 17, and 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Pathak and Zhang as applied to claims 1-8, 10, 11, 14, 15, 19, and 20 above, and further in view of Mihajlovic et al. (Multifunct. Mater., 2021).
Pathak and Zhang are discussed above.
Neither Pathak nor Zhang teach polysaccharide crosslinking by metal ion coordination of carboxylic acid functional groups contained on the polysaccharide backbone.
Mihajlovic discloses hydrogels of hyaluronic acid that make use of a variety of bi-valent metal ions such as Ba2+ to fabricate supramolecular hydrogels by polysaccharide crosslinking using metal ion coordination of carboxylic acid functional groups contained on the polysaccharide backbone. (page 10, bottom).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to incorporate metal ion crosslinking of carboxylic acid groups on the polysaccharide backbone, as taught by Mihajlovic, into the hydrogel structure of Zhang. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because metal ion coordination is a well-known strategy to form crosslinked hydrogels from polysaccharides containing carboxylic functional groups.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAMES DAVID BURGESS whose telephone number is (571)270-5640. The examiner can normally be reached Monday - Friday 8:30AM - 5:00PM.
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/JAMES D BURGESS/Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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